5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5h-(1) benzopyrano(3,4-d)pyridine as an analgesic agent

ABSTRACT

A METHOD OF RELIEVING PAIN IN MAMMALIAN PARTIENTS COMPRISING ADMINISTERING A THERAPEUTICALLY EFFECTIVE AMOUNT OF 5,5-DIMETHYL - 10 - HYDROXY-8-(3-METHYL-2-OCTYL)-2-(2PROPYNYL) - 1,2,3,4 - TETRAHYDRO - 5H - (1)BENZOPYRANO(3,4-D)PYRIDINE TO A PATIENT.

United States Patent 3,795,736 5,5-DIMETHYL 10 HYDROXY-8-(3-METHYL-2- 0CTYL)-2-(2-PROPYNYL) 1,2,3,4-TETRAHYDRO- H-[1] BENZOPYRANO[3,4-d]PYRIDINE AS AN ANALGESIC AGENT Louis Selig Harris, Chapel Hill, N.C., and Harry George Pars, Lexington, and Raj Kumar Razdan, Belmont, Mass., assignors to Sharps Associates, Cambridge, Mass. No Drawing. Filed Aug. 24, 1972, Ser. No. 283,435 Int. Cl. A61k 27/00 US. Cl. 424-263 2 Claims ABSTRACT OF THE DISCLOSURE A method of relieving pain in mammalian patients comprising administering a therapeutically efiective amount of 5,5-dimethyl hydroxy-8-(3-methyl-2-octyD-2-(2- propynyl) 1,2,3,4 tetrah'ydro 5H [l]benzopyrano- [3,4-d1pyridine to a patient.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a method of relieving pain using 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-(2 propynyl) 1,2,3,4 tetrahydro 5H [1]benzopyrano- [3,4-d] pyridine as the analgesic agent.

While there are a number of currently available analgesic agents on the market, the search for improved analgesic agents has been continued, since a number of the more potent agents are classified as narcotics. That is, if it is necessary for patients to take analgesic agents such as codeine, morphine and the like over a prolonged period of time, the addiction liability is high. The present invention provides an analgesic agent which appears to be free from addiction liability.

5,5 dimethyl 10 hydroxy-8-(3-methyl-2-octyl)-2-(2- propynyl) 1,2,3,4 tetrahydro 5H [l]benzopyrano- [3,4-d]pyridine has previously been reported to be useful as a central nervous system depressant (see US. Pat. No. 3,576,798). It has now been found that the compound possesses analgesic activity.

The compound useful in the practice of this invention is represented by the formula The compound can be prepared according to the method taught in US. Pat. No. 3,576,798.

In the practice of this invention, 5,5-dimethyl-10-hydroxy-8-(3-methyl 2 octyl) 2 (2-propynyl)-1,2,3,4- tetrahydro-5H-[ 1]benzopyrano [3,4-d] pyridine is administered to mammalian patients suffering from pain in dosages of from 0.01 to 0.2 mg./kg. I.V. and from 2.5 to 40 mg./kg. p.o., preferably in divided doses, i.e., three to four times daily.

The analgesic activity of the compound was evaluated in the hot plate analgesic test, the acetic acid writhing test and the rat tail flick study.

In the hot plate analgesic test carried out according to the method of Woolfe, G. and MacDonald, A. D., J. Pharmacol. Exper. Therap., 80, 300 (1944), 5,5-dimethyl- 10-hydroxy-8-(3-methyl-2-octyl) 2 (2 propynyl)-l,2, 3,4-tetrahydro-5H-[1]benzopyrano[3,4d]pyridine has an I.V. ED of 0.16 mg./kg. (95 C.L.=0.11 to 0.20) and an oral ED of 7.7 mg./kg. (95% C.L.=4.1 to 12.7).

3,795,736 Patented Mar. 5, 1974 [Morphine exhibits an intravenous ED value in mice of 0.009 mg./kg. C.L.'=0.006 to 0.014) and an oral ED value of 12.6 mg./kg. (95% C.L.=9'.7 to 16.4)].

Analgesic activity was also evaluated via the acetic acid writhing method, modified from that described by Whittle Brit. J. Pharmacol., 22, 296 (1964). The number of writhes were counted for a 20 minute period beginning 5 minutes after the injection of the acid. Analgetic potency was calculated from the diiference between the test groups and their controls. The compound exhibits an intravenous ED value of 0.0-3 mg./kg. (95% C.L.'=0.02 to 0.04) and an oral ED' value of 4.3 mg./kg. (95% C.L. =3.2 to 5.9).

The analgesic activity of the compound useful in the practice of this invention in the acetic acid writhing test is summarized in the following tables:

TABLE I Acetic acid writhing test in mice (I.V.)

Dose mg./kg. p.o.: Percent inhibition The oral ED of codeine phosphate is 15.6 mg./kg. (95% C.L.=9' to 23).

Analgesic activity was also exhibited in the rat tail fiick study (DAmour and Smith, J. Pharmacol. Exper. Therap., 72: 74, 1941). The compound exhibits an intravenous ED value of 0.13 (95% C.L.=0.07 to 0.18) and an oral ED value of 13.8 mg./kg. (95% C.L.==4.5 to 23.9).

The compound useful in the practice of this invention can be formulated into various pharmaceutically acceptable dosage forms such as tablets, capsules, pills and the like for immediate or sustained release, by combining the compound with a suitable pharmaceutically acceptable carrier or diluent according to methods well known in the art. Such dosage forms may additionally include lubricants, excipients, binders, fillers, flavoring and sweetening agents and other therapeutically inert ingredients necessary for the formulation of the desired preparation.

We claim:

1. A method of relieving pain in a mammalian patient suffering therefrom comprising administering to said patient a therapeutically effective amount of 5,5-dimethyl-lO-hydroxy-S-(3-methyl-2-octyl) 2 (2-propynyl)-1,2,3,4-tetrahydro-5H-[ 1 benzopyrano[ 3,4-d] pyridine.

2. The method of claim 1 wherein said compound is administered in dosages of from 0.01 to 40 mg./kg. of body weight daily.

References Cited UNITED STATES PATENTS 3,576,798 4/1971 Pars et a1. 260240 STANLEY J. FRIEDMAN, Primary Examiner @3 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION L.S., Harris et al. I

Inventofls rs in the above-ideritified patent It. is certified that error appea by corrected as shown below:

and that: said Letters Patent are here Col. 1, lines*4354, the lower left portion of the structural formula should ,be 1 s I 3. 0 Col. 2, line "p.o." should be I.V.-.

-- S'igried and sealed this 9th day of July 197A.

(SEAL) Attest: v McCOY lyl. GIBSON, JR. c. MARSHALL DANN Attesting Officer Commissioner of Patents 

